Pyrrolidyl-alkyl esters of 2, 6-dimethyl-4-propoxybenzoic acids



United States Patent F PYRROLIDYL-ALKYL ESTERS OF 2,6,-.DI1VIETH YL- 4-PROPOXYBENZOIC ACIDS William Bradley Reid, Jr., Kalamazoo, Micl1., assiguor to The Upjohn Company, Kalamazoo, Mich., a corpo-. ration of Michigan No Drawing. Application July 8, 1949 Serial No. 103,755

9 Claims. (Cl. 260326.3)

This invention relates to pyrrolidyl-1 and (alkylpyrrolidyl-l)-alkanol esters of 2,6-dimethyl-4rpropoxybenzoic acids, and to their acid addition salts.

The esters of this invention are represented by the following structural formula:

wherein R is a member of the group consisting of normal propyl and isopropyl radicals, R is a member of the group consisting of pyrrolidyl-1 and lower-alkyl substituted pyrrolidyl-l radicals, and n is an integer from 2 to 5, inclusive.

The esters of the invention are high boiling liquids which are readily soluble in most organic solvents but insoluble in water. Their acid addition salts, such as the hydrochloride, hydrobromide, sulfate, nitrate, acetate, and citrate, are generally crystalline solids with well-defined melting points and are readily soluble in cold water, methanol, or ethanol; moderately soluble in isopropanol, ethyl acetate or methyl ethyl ketone; and insoluble in the common aliphatic, cycloaliphatic, and aromatic hydrocarbon solvents.

Members of this new group of compounds have been prepared and found to have value as local anesthetics, being active both subcutaneously and topically.

The free basic esters of the invention can be prepared readily by reacting an acid chloride, having the formula:

ROQCOO1 wherein R, R and n have the values previously given. The corresponding acid bromides can also be used, if desired, although the method of preparing the compounds of this invention will be described with particular reference to use of the acid chlorides, which are prepared readily and in excellent yield by treating the corresponding acid with thionyl chloride for a period of from one to several hours. The reaction can be carried out conveniently at the reflux temperature of the mixture. An excess of thionyl chloride is usually employed and the excess subsequently removed by distillation at a reduced pressure, leaving the acid chlo ride as a residue which is usually sufficiently pure for use without further purification, but which can be fractionally distilled for purification, if desired. Acid bromides are prepared from the acids in a similar fashion using thionyl bromide.

The acids used in the form of their bromides or chlorides in preparing the esters of the invention, can be synthesized by the following procedure: bromination of 3,5-dimethylphenol to produce 4-bromo-3,5-dimethylphenol, etherification to produce a 4 bromo 3,5 dimethylphenyl propyl ether, reaction with magnesium. to form a Grignard comp e a na n; andQa idifiwt Q h f he e s eps;

is known and can be performed as described in the prior r and as furthe esc ibed in e exa le e y l l alkanols us d in re rin t e s. of the invention may be prepared conveniently in several ways. For examples, a haloalkanol may be reactedwith' In certain in-.; stances, it is advantageous firstto condense pyrrolidineor pyrrolidine or with an alkyl pyrrolidine.

hydroxyalkyl succinimide, or with a gamma-keto acid toform an N-hydroxyalkylpyrrolidone. These ketones or esters are then allowed to react withilithium aluminum-- hydride in absolute ether to produce the desired pyrrolidyl alkanol or alkyl-pyrrolidyl alkanol. Pyrrolidyl alkanols also may be prepared by condensinga selected pyrrolidonel compound with formaldehyde and a suitable aliphatic aldehyde to produce an N-py-rrolidylaldehyde, which is readily reduced with aluminumisopropoxide in isopropyl alcohol to the desired pyrrolidyl alkanol or alkylpyrrolidyl alkanol.

The reaction of an acid chloride and a pyrrolidylallcanolj can be carried out conveniently by mixing the two substances together in the-presence of an inert diluent, such as dry xylene or other hydrocarbon, or in the absence ofsuch diluent. Reaction usually occurs at ordinarytemperatures and can be accelerated and brought substantially to completion by finally refluxing the mixture for about thirty minutes or longer. Upon allowing the reaction mixture to cool, the hydrochloride of the basic ester generally crystallizes and can be separated from any inert diluent. by filtration, The free ester can be recovered and purifiedv by dissolving the crude hydrochloride in water, extraetingthe solutionwith ether to remove any remaining inert dilu; ent orothc. W itten-insoluble substances, alkalizing the solu: tion with aqueous sodium hydroxide, extracting with ether or other suitable organic liquid, and eventually distilling the extract to volatilize the solvent. The basic esters can be distilled uncler'reduced pressure to obtain a higher (1Q: gree of purity, if desired, or the salts can be purified hy recrystallization from a suitable solvent, such aleohol; ethyl acetate, methyl ethyl ketone, or the like. I

Acid addition salts of the basic esters, such as the hydrochloride, hydrobromide, sulfate, phosphate, acetatgciv. trate, tartrate, benzoate, lactate, picrate, and other agid addition salts can be easily prepared by allowing the ester to react with a selected aeid in a solvent suehjas aleohol, or a mixture of alcohol and ethylacetate. Upon di stil-" propanol, a pyrrolidyl-butanol, or a pyrrolidyl-pentanol.

The r n 9 n o t e a en swuaQHzm nbe straight or branched. The pyrrolidine ring can be unsub-' stituted or it can eontain one or more loWer-alkyl groups.

Lower-alkyl as used in this specification and the appended claims, includes alkyl groups having one to five carbon atoms, "inclusive. Representative groups which may be substituted on the pyrrolidyl ring are, for

example, methyl, ethyl, propyl, isopropyl, butyl, second ary-butyl, tertiary-butyl, pentyl, isopentyl, and the lile.

, l atented Oct. 4, 19 .5-

It is to be understood that the invention is not limited to alkyl-pyrrolidyl esters wherein the pyrrolidyl ring contains a single lower-alkyl substituent, but that the pyrrolidyl ring may contain a plurality of such substituents. The pyrrolidyl ring is in all cases attached to the alkylene group through the nitrogen atom.

Representative pyrrolidyl-alkanols, which, among others, can be used in preparing esters of the invention, include:

2- (pyrrolidyl-1 ethanol 2- 2-methylpyrrolidyl-1 -ethanol 2- 3-methylpyrrolidyl-l -ethanol 2- (2,3-dimethylpyrrolidyl-1 -ethanol 2- (2,4-dimethylpyrrolidyl-1 -ethanol 2-(2,5-dimethylpyrrolidyl-1 -ethanol 2-( 3 ,3-dimethylpyrrolidyl-1 -ethanol 2-( 3 ,4-dimethylpyrrolidyl-1 )-ethanol 2- (2,4,4-trimethylpyrrolidyl-1 -ethanol 2-(2-ethylpyrrolidyl-1)-ethanol 2- (2-pentylpyrrolidyl-1 )-ethanol 2- [2- n-propyl) pyrrolidyl- 1 ]-ethanol 2- (pyrrolidyl-1 )-propanol-1 3- (pyrrolidyl-1 )-propanol-1 2-methyl-2- (pyrrolidyl-1 -propanol-1 3-(2-methylpyrrolidy1-1 )-propanol-1 2-methy1-3- (pyrrolidyl-1 )-propanol-1 2,2-dimethyl-3-(pyrrolidyl-1)-propanol-1 1- (pyrrolidyl-l )-prop anol-Z 1- (2,4-dimethylpyrrolidyl-1 )-propanl-2 1- (2,5-dimethylpyrrolidyll -propano1-2 3- (pyrrolidyl-1 -butanol1 4- (pyrrolidyl-1 -hutanol1 3-(pyrrolidyl-1)-butanol-2 1- (pyrrolidyl-1 -butanol-3 1- (pyrrolidyl- 1 -pentanol-4 Although the preferred method of preparing the com pounds of the invention comprises reacting a 2,6-dimethyl- 4-propoxy-benzoyl chloride with a pyrrolidyl alkanol, because of the high yield of pure product obtained, it should be pointed out that the esters may also be prepared in other ways apparent to those familiar with the art. Thus, for example, an alkali metal salt of a 2,6-dimethyl-4-pyropoxybenzoic acid can be heated with a suitable pyrrolidyl-alkyl halide, preferably in a suitable solvent such as ethanol, isopropanol, isopropyl ether, or butanol, and the desired ester isolated from the reaction mixture.

Free basic esters within the scope of the invention include, among others:

2- (pyrrolidyl-1)-ethyl 2,6-dimethyl 4 (n-propoxy)benzoate 2- (pyrrolidyl-1 )-ethyl 2,6-dirnethyl-4-isopropoxybenzoate Z-(S-methylpyrrolidyl-l)-ethy1 2,6-dimethyl 4 (n-propoxy)benzoate 2-(3-methylpyrrolidyl-1)-ethyl 2,6 dimethyl 4 isopropoxybenzoate 2- 2,3-dimethylpyrrolidyl-l )-ethyl 2,6-dimethyl-4- (n-propoxy) benzoate 2-(2,3-dimethylpyrrolidyl-1 )-ethyl 2,6-dimethyl-4-isopropoxybenzoate 2-(2-methylpyrrolidyl-1)-ethy1 2,6 dimethyl 4 (n-propoxy) benzoate 2-(2-rnethylpyrrolidyl-1)-ethyl 2,6 dimethyl 4 isopropoxybenzoate 2-(2,4-dimethylpyrrolidyl-1 -ethyl 2,6-dirnethyl-4- (n-propoxy) benzoate 2- (2,4-dimethylpyrrolidyl-1 -ethyl 2,6-dimethyl-4-isopropoxybenzoate 2- 2,5 -dimethylpyrrolidyl-1 -ethy1 2,6-dimethyl-4 (n-propoxy) benzoate 2- (2,5-dimethylpyrrolidyl-1 -ethyl 2,6-dimethyl-4-isopropoxybenzoate 2 3,3-dimethylpyrrolidyl-1 -ethyl 2,6-dimethyl-4- (n-propoxy) benzoate 2- (3 ,3-dimethylpyrrolidyl-1 -ethy1 2,6-dimethyl-4-isopropoxybenzoate 2-(3,4-dirnethylpyrrolidy1-1)-ethy1 2,6-dimethyl-4-(n-propoxy) benzoate.

2-( 3,4-dimethylpyrrolidyl-1 -ethyl 2,6-dimethyl-4-isopropoxybenzoate 2- 2,4,4-trimethylpyrrolidyl-1 -ethyl prop oxy) benzoate 2- (2,4,4-trimethylpyrrolidyl-1 -ethyl propoxybenzoate 2-(2-ethylpyrrolidyl-1 )-ethyl 2,6-dimethyl-4- (n-propoxy) benzoate 2- 2-ethylpyrrolidyl-1 -ethy1 2,6-dimethyl-4-isopropoxybenzoate 2 (pyrrolidyl 1) 1 propyl 2,6 dimethyl 4 (npropoxy)benzoate 2 (pyrrolidyl 1) 1 propyl 2,6 dimethyl 4 isopropoxybenzoate 3 (pyrrolidyl 1) 1 propyl 2,6 dimethyl 4 (npropoxy) benzoate 3 (pyrrolidyl 1) 1 propyl 2,6 dimethyl 4 isopropoxybenzoate 2 methyl 2 (pyrrolidyl 1) 1 propyl 2,6 dimethyl-4-( n-propoxy) benzoate 2 methyl 2 (pyrrolidyl 1) 1 propyl 2,6 dimethyl-4-isopropoxybenzoate 3 (2 methylpyrrolidyl 1) 1 propyl 2,6 dimethyl- 4-(n-propoxy)benzoate 3 (2 methylpyrrolidyl 1) 1 propyl 2,6 dimethyl- 4-isopropoxybenzoate 2 methyl 3 (pyrrolidyl 1) 1 propyl 2,6 dimethyl-4-(n-propoxy)benzoate 2 methyl 3 (pyrrolidyl 1) l propyl 2,6 dimethyl-4-isopropoxybenzoate 2,2 dimethyl 3 (pyrrolidyl 1) 1 propyl 2,6-

dimethyl-4-(n-propoxy)benzoate 2,2 dimethyl 3 (pyrrolidyl 1) 1 propyl 2,6 dimethyl-4-isopropoxybenzoate l (pyrrolidyl 1) 2 propyl 2,6 dimethyl 4 (npropoxy) benzoate 1 (pyrrolidyl 1) 2 propyl 2,6 dimethyl 4 isopropoxybenzoate 1 (2,4 dimethylpyrrolidyl 1) 2 propyl 2,6 dimethyl-4-(n-propoxy) benzoate 1 (2,4 dimethylpyrrolidyl 1) 2 propyl 2,6 dimethyl-4-isopropoxybenzoate l (2,5 dimethylpyrrolidyl 1) 2 propyl 2,6 dimethyl-4-isopropoxybenzoate 1 (2,5 dimethylpyrrolidyl 1) 2 propyl 2,6 dimethyl-4- n-propyl) benzoate 2,6-dimethyl-4-iso- 3 (pyrrolidyl 1) 1 butyl 2,6 dimethyl 4 (npropoxy)benzoate 3 (pyrrolidyl 1) 1 butyl 2,6 dimethyl 4 isopropoxybenzoate 4 (pyrrolidyl 1) 1 butyl 2,6 dimethyl 4 (npropoxy)benzoate 4 (pyrrolidyl 1) 1 butyl 2,6 dimethyl 4 isopropoxybenzoate 3 (pyrrolidyl 1) 2 butyl 2,6 dimethyl 4 (npropoxy) benzoate 3 (pyrrolidyl 1) 2 butyl 2,6 dimethyl 4 isopropoxybenzoate 1 (pyrrolidyl 1) 3 butyl 2,6 dimethyl 4 (npropoxy benzoate 1 (pyrrolidyl 1) 3 butyl 2,6 dimethyl 4 isopropoxybenzoate 1 (pyrrolidyl 1) 4 pentyl 2,6 dimethyl 4 (npropoxy)benzoate 1 (pyrrolidyl 1) 4 pentyl 2,6 dimethyl 4 isopropoxybenzoate The following preparations and examples are given to illustrate certain methods by which some of the starting materials and compounds of the present invention can be prepared, but are not to be construed as limiting.

2,6-dimethyl-4-(n- PREPARATION l.ETHYL ALPHA( PYRROLIDYL-l PROPIONATE To a stirred solution of 181 grams of ethyl alphabromopropionate in 200 milliliters of benzene, 148 grams of pyrrolidine was added at a substantially uniform rate over a period of 45 minutes. The reaction was quite vigorous, causing the solvent to boil. After all of the pyrrolidine had been added, the solution was heated under reflux for an hour, cooled, poured into 400 milliliters of ice-water, acidified with dilute aqueous hydrochloric acid, and the resulting two layers separated. The aqueous layer was washed with ether, made strongly alkaline with cold aqueous sodium hydroxide, and extracted four times with 200 milliliter portions of either. The ether extracts were combined, dried, the solvent removed, and the residue distilled at a reduced pressure of about 12 millimeters of mercury absolute. There was thus obtained 156.7 grams (91.5 percent of the theoretical) of ethyl alpha-(pyrrolidyl-l)-propionate, boiling at 84 degrees centigrade at a pressure of 12 millimeters of mercury absolute.

PREPARATION 2.Z(PYRROLIDYL-1)-PROPANOL-1 To a mixture of 7.6 grams of lithium aluminum hydride in 250 milliliters of dry ether, 61.7 grams of ethyl alpha-(pyrrolidyl-l)-propionate was added slowly, causing gentle refluxing of the ether. The mixture was then allowed to stand for a few minutes without cooling, 20 milliliters of water added dropwise and the mixture then cooled to about ten degrees centigrade by adding ice. After acidifying with aqueous hydrochloric acid, the aqueous layer was separated, washed with ether, and made strongly basic with concentrated aqueous sodium hydroxide. The basic solution was then extracted repeatedly with ether, ether extracts combined, dried with anhydrous potassium carbonate, the ether removed, and the residual oil fractionally distilled. There was thus obtained 38.1 grams of Z-(pyrrolidyl-l)-propanol-1, boiling at 80 degrees centigrade at a pressure of 11 millimeters of mercury absolute, and having an index of refraction, n of 1.4758.

PREPARATION 3 Following substantially the procedure given in Preparations 1 and 2, the following alcohols were prepared:

1. 2-methyl-3-(pyrrolidyl-1)-propanol-1, boiling at 91 degrees centigrade at a pressure of 12 millimeters of mercury absolute; n' of 1.4620.

2. 3-(pyrrolidyl-1)-butanol-l, boiling at 114 degrees centigrade at a pressure of 21 millimeters of mercury absolute; n of 1.4742.

3. 3-(pyrrolidyl-1)-butanol-2, boiling at 79 degrees centi-.

grade at a pressure of 13 millimeters of mercury absolute; n of 1.4610.

4. l-(pyrrolidyl-l)-butanol-3, boiling at 87 degrees centigrade at a pressure of 15 millimeters of mercury absolute; 11 of 1.4611.

PREPARATION 4.-3-(PYRROLIDYL-l)-PROPANOL-l A mixture consisting of 50.7 grams of sodium hydroxide, 45.7 grams of water, and 60.5 grams of pyrrolidine, was prepared, stirred vigorously, and 100 grams of 3-chloropropanol-1 added thereto at a rate such that the temperature was maintained between about 75 and 100 degrees centigrade. When addition had been completed, the mixture was stirred for an additional thirty minutes and allowed to stand for several hours. Sufficient solid sodium hydroxide was then added to saturate the mixture, and resulting oily layer separated. The aqueous layer was extracted with benzene, the benzene extract added to the oily layer, and the mixture fractionally distilled. There was thus obtained 65.5 grams of 3-(pyrrolidyl-l)-propanol-1, boiling at 115 degrees centigrade at a pressure of 43 millimeters of mercury absolute, and having an index of refraction, n of 1.4701.

PREPARATION 5.?4-(PYRRoL1nYL-1)-aurANoL-1 Following substantially the procedure given in Preparation 4, 4-(pyrrolidyl-1)-butanol-1, having a boiling point of 113 degrees centigrade under a pressure of 12 millimeters of mercury absolute; n of 1.4705, was prepared.

PRaPA ATroN 6.-.2MI 5 THYL.-2-(PYRROLIDYL-l)- PROPANOL-l A mixture of 44.6 grams of 2-amino-2-methyl-propanel-1, 108 grams of tetramethylene dibromide, and 200 milliliters of toluene was refluxed for three hours, 84 grams of sodium bicarbonate added, and the refluxing continued for an additional fifteen hours. The mixture was then cooled to about 25 degrees centigrade, milliliters of aqueous fifty percent sodium hydroxide-added, the resulting organic layer removed, suflicient water added to dissolve the salt, and the aqueous solution ex-v tracted continuously with ether for nine hours. The ether extract and the organic layer were combined, dried over anhydrous potassium carbonate and distilled. The distillate, melting at 27.5 degrees centigrade, was dissolved in dilute acid and treated with aqueous sodium nitrite to remove any secondary amines. After extracting with ether, the aqueous solution was made basic with aqueous sodium hydroxide and extracted three times withlOO- milliliter portions of ether. The ether extracts were combined, dried, the ether removed and the residue distilled under'a reduced pressure of about 12 millimeters of mercury absolute. There was thus obtained 54 grams (75.5 percent of the theoretical) of 2-methyl-2-(pyrrolidyl-1)- propanol-1, boiling at 87 deg-reescentigrade under a pressure of 12 millimeters of mercury absolute, and having an index of refraction, n of 1.4720.

PRElA TION 7 ..2 ,2-DIMETHYL-3(PYRR0LIDYL-l)- PROPIONALDEHYDE' A m xtu f g ams f pyrr i 8 m it rs of. concentrated hydrochloric acid, and 81 milliliters of 37 percent formalin was heated to reflux, 79.3 grams of iso-. butyraldehyde added at a substantially uniform rate over a period of threequarters of an hour, boiling under reflux continued for an additional hour, 50 milliliters of 37 fi ment-formalin added, and the mixture refluxed for another hour and a quarter. After standing for three days, the mixture was made strongly basic with 40 percent sodium hydroxide and extracted five times with milliliter portions of ether. The ether extracts were com, bined, dried over anhydrous potassium carbonate, solvent removed, and the residue fractionally distilled at a reduced pressure of about 32 millimeters of mercury absolute. There was thus obtained 65.7 grams (42.3 percent of the theoretical) of 2,2-dimethyl-3-(pyrrolidyl-l)- propionaldehyde, boiling at 97 degrees centigrade at a PREPARAT N 8.-2,2DIMETHYL3{PYRROLIDYL-D- PROPANOL-l A mixture of 61.5 grams of 2,2-dirnethyl-3-(pyrrolidyl- -1)-propionaldehyde and 350 milliliters of isopropanol was removed from 40.8 grams of aluminum isopropoxide by slow distillation through an eflicient column. After six hours of distillation, the distillate gave a negative test for acetone. The dark residue was then cooled and 200 milli-' liters of 10 percent sodium hydroxide added. The organic layer was separated from the aqueous layer, and saturated with aqueous potassium carbonate to form two layers. The aqueous fraction was separated, combined with the aqueous layer obtained previously, and extracted six times with 100-milliliter portions of ether. The ether extracts were combined and dried over anhydrous potassium carbonate. The ether was removed and the residue fractionally distilled at a reduced pressure of about 26 millimeters of mercury absolute. There was thus obtained 25.6

grams (41.7 percent of the theoretical) of 2,2-dimethyl- 3-(pyrrolidyl-l)-propanol-l, boiling at 111 degrees centigrade at a pressure Of 26 millimeters of mercury absolute, and having an index of refraction, 11 of 1.4609.

PREPARATION 9.1-(PYRRoLIoYL-1)-PENTANoNE-4 A solution of 150 grams of 2-(pyrrolidyl-1)-ethyl chloride in 100 milliliters of benzene was added dropwise to a suspension of the sodium enolate of ethyl acetoacetate (obtained from 147 grams of ethyl acetoacetate and 26 grams of metallic sodium) in one liter of boiling benzene, and the mixture heated under reflux for ten hours. The mixture was cooled to about 25 degrees centigrade, and a solution of 75 milliliters of concentrated sulfuric acid in 160 milliliters Of water and 140 grams of ice added thereto. The resulting aqueous layer was separated and washed with benzene. The aqueous acidic sOlution of ethyl alpha-[beta-(pyrrolidyl 1)-ethyl]-acetoacetate sulfate was heated under reflux for seventeen hours, cooled to about degrees centigrade, 430 milliliters of cold thirty percent sodium hydroxide solution added, and the resulting oily organic layer separated. The aqueous layer was extracted three times with 100- milliliter portions of benzene, the organic layer and the benzene extracts combined, dried, the benzene removed, and the residue distilled at a reduced pressure of about 12 millimeters of mercury absolute. There was thus obtained 129 grams of l-(pyrrolidyl-l)-pentanone-4, distilling at 92-98 degrees centigrade at 11-13 millimeters of mercury pressure absolute. Redistillation gave 98.2 grams of l-(pyrrolidyl-l)-pentanone-4 (n of 1.4589), distilling at 93-95 degrees centigrade at a pressure of 11 millimeters of mercury absolute.

PREPARATION 10.-1-(PYRROLIDYL-1)-PENTANoL-4 A solution of 65.5 grams of 1-(pyrrolidy1-1)-pentanone-4 in 60 milliliters of methanol was hydrogenated at 1100 pounds pressure and 100 degrees centigrade in the presence of five grams of Raney nickel catalyst. The reaction took about three hours to absorb nearly the theoretical quantity of hydrogen. After removal of the catalyst and solvent, the residue was distilled under a reduced pressure of about 12 millimeters of mercury. There was thus obtained 57.2 grams (85 percent of the theoretical) of l-(pyrrolidyl-l)-pentanol-4, boiling at 111 degrees centigrade at a pressure of 12 millimeters of mercury absolute, and having an index of refraction, n of 1.4652.

PREPARATION 1 1.1-(2-HYDROXYETHYL)-5-ME'I'HYL PYRROLIDONE-Z A suspension of 0.2 gram of platinum oxide catalyst in 25 milliliters of absolute ethanol was reduced to platinum, a solution of 34.8 grams of levulinic acid and 37.8 grams of ethanolamine in 75 milliliters of absolute alcohol added, and the mixture hydrogenated at about 50 pounds pressure and room temperature for about four hours, at the end of which time the theoretical amount of hydrogen had been absorbed. After the catalyst and solvent had been removed, the residue was fractionally distilled. There was thus obtained 42.5 grams (100 percent of the theoretical) of 1-(2-hydroxyethyl)-5-methyl-pyrrolidone-2, boiling at 167 degrees centigrade at a pressure of 12 millimeters of mercury absolute and having an index of refraction, 12 of 1.4900.

PREPARATION l2.2(2-ME'I'HYLPYRROLIDYL-l)-ETHANOL By a procedure similar to that described in Preparation 2, fifty-One grams of l-(2-hydroxyethyl)-5-methyl- 2-pyrrolidone was reduced with 18 grams of lithium aluminum hydride in 400 milliliters of ether. Distillation gave grams (76 percent of the theoretical) of 2-(2- methylpyrrolidyl-l)-ethanol, boiling at 87 degrees centigrade at a pressure of 16 millimeters of mercury absolute, and having an index of refraction, 22 of 1.4680.

PREPARATION 13 By a procedure similar to that described in Preparations l1 and 12, the following compounds were prepared:

1. 2-(2,3-dimethylpyrrolidyl-l)-ethanol, boiling at 86 degrees centigrade at a pressure Of 13 millimeters of mercury absolute, index of refraction, 21 of 1.4661.

2. 3-(2-methylpyrrolidyl-1)-propanol-1, boiling at degrees centigrade at a pressure of 18 millimeters of mercury absolute, index of refraction, 11 of 1.4672.

PREPARATION l4.N-(2-HYDROXYETHYL) -ALPHA- METHYLsuccINIMIDE PREPARATION 15 .2-(3-METIIYLPYRROLIDYL) -ETHANOL By a procedure similar to that described in Preparation 2, 62.8 grams of N-(Z-hydroxyethyl)-alpha-methylsuccinimide was reduced with 30 grams of lithium aluminum hydride. Upon fractional distillation, there was obtained 35 grams (68.1 percent of the theoretical) of 2-(3-methylpyrrolidyD-ethanol, boiling at 86 degrees centigrade at a pressure of 16 millimeters of mercury absolute, and having a refraction index, 11 of 1.4680.

PREPARATION 16 By a procedure similar to that described in Preparations 14 and 15, the following alcohols were prepared:

1. 2-(3,3-dimethylpyrrolidyl-1)-ethanol, boiling at 81 degrees centigrade at a pressure of 13 millimeters of mercury absolute, index of refraction, 11 of 1.4580.

2. 2-(3,4-dimethylpyrrolidyl-1)-ethanol, boiling at 86 degrees centigrade at a pressure of 12 millimeters of mercury absolute, index of refraction, n of 1.4594.

3. 2-(2,4,4-trimethylpyrrolidyl-1)-ethanol, boiling at 84 degrees centigrade at a pressure of 14 millimeters of mercury absolute, index of refraction, 11 of 1.4535.

PREPARATION 17 .4-BROMo-3,S-DIMETIIYL-PIIENOL A solution of 160 grams of bromine, dissolved in 700 milliliters of glacial acetic acid, was added, with stirring, at a substantially uniform rate over a period of two hours to 122 grams of meta xylenol dissolved in 600 milliliters of glacial acetic acid maintained at 17-20 degrees centigrade. The reaction mixture was then poured into a mixture of two kilograms of 50 percent sodium hydroxide solution and 15 kilograms of crushed ice. The solid which separated was filtered oif, dried, and recrystallized from n-pentane. There was thus Obtained grams of 4-brorno-3,S-dimethyl-phenol, melting at 112-114 degrees centigrade.

PREPARATION l8.-Z,6-DIMETHYL-4-(N-PROPOXY)- BRoMoEENzENE To a solution of 55.2 grams of sodium metal, dissolved in 800 milliliters of absolute n-propanol, was added 482.6 grams of 4-bromo-3,S-dimethyl-phenol, followed by 615.0 grams of n-propyl bromide. The mixture was heated under reflux for five hours, excess n-propylbenzene and n-propyl alcohol removed by distillation, and the sodium bromide filtered off. The filter cake was washed with ether, the ether extract combined with the filtrate, dried, the solvent removed by distillation, and the sodium bromide filtered off. The filter cake was Washed with ether, the ether extract combined with the filtrate, dried,

[9 the solvent removed by distillation, andthe-residue dis tilled under a reduced pressure. There was thus obtained 441.9 grams of 2,6-dimethyl-4-(n-propoxy)-brornobenzene, distilling at 81 degrees centigrade ataprfessur'e" of 0.15 millimeterof mercury absolute, and havin gjan index of refraction, lib of 1.5440. i

Analysis: j I

Calculated for C11H15 OBIZ Br, 328 Found: 32

PREPARATION 19.-2, 6-DIMETIIYL-4-(N-PRoPoxr) BENZOIC ACID 1..

To a mixture of 46.2 grams of magnesium turnings and one liter of absolute diethyl ether was added, with-stirring, over a period of .five hours, 439.2 grams ofT2,6-dimethyl- 4-(n-propoxy)bromobenzene dissolved in 750 milliliters of anhydrous diethyl ether. After the reaction was complete, as shown by disappearance of the magnesium; the reaction mixture was cooled, poured onto about' jone' kilogram of finely'divided solid carbon dioxide andall'owed Analysis:

Calculated for C zHisOaz C, 69.3;H,7.75 Found: 69.4; 714.0 PREPARATION 20.2,G-DIMETHYL-4-(Nr-PROPOXY)- BENZOYL CHLORIDE v A mixture of 328 grams of thionyl chloride, 255 grams of 2,6-dimethyl-4-(n-propoxy)benzoic acid, and 'ISO-millia liters of benzene was heated under anhydrous reflux for 18 hours, concentrated under reduced pressure to remove the excess of thionyl chloride and benzene, and t'he' residue distilled. There was thus obtained 205 grams'of 2,6- dimethyl-4-(n-propoxy)-benzoyl chloride, boiling at 131 to 132 degrees centigrade at a pressure of 12 millimeters of mercury absolute.

PREPARATION V 21 .2, 6-DIMETIIYL-4-IS0PRoPoxYB o o- BENZENE In a manner-essentially that described in Preparation 18, 471 grams of 2,6 dimethyl-4 isopropoxybromobenzene, boiling at 131 to 132 degrees centigrade at a pressure of 11 millimeters of mercury absolute, was obtained-horn 482.6 grams of 4-bromo-3,5-dimet-hylphenol, 5.2 grams of sodium, and 492 grams of isopropyl biornidejn 1.5 liters of anhydrous isopropanol. I Analysis: Calculated for C11HI5OBr: Br, 32.8

Found: I 32.7 v PREPARATION 22.2,'6 DIMEmYL-4-Isorkoi oirmrrkorc I ACID In a manner essentially that described in Preparation 19., 260 grams of 2,6-dimethyl-4-is'opropoxybenzoic .ac'id, melting at 121 to 122 degrees centigrade, was obtained from 404.4 grams of 2,6-dimethyl-4-isopropoxybrorno benzene, 41.3 grams of magnesium metal, 1.75'liters of absolute ethyl ether, and one kilogram ofpowdered solid carbon dioxide.

PREPARATION 23. 2,6-mMErm-4asomibpbxrimnzor CHLORIDE In a manner essentially that described in Preparation- 20, 204.2 grams of 2,6-dimcthyl-4-isopr0poxybenzoyl chloride, boiling at 141 to 142 degrees centi'gra'd'e at a pressure of ten millimeters of mercury absolute; was obtained from 255 grams of 2,6-dimethyl-4-isopropoxybenzoic aoid, .328 grams' of thionyl unease; and i niilii-i liters of benzene.

. olutio o rams 9 2,-( ,-.d r e l ay1gy1:rs lid)' ethanol in 25 milliliters "of dry iiietliyl ethyl ketone added to a solution of 11.4 grams of 2,6-dimethyl 4-(n-' propoxy)benzoyl chloride in 25 millilitersof dry' nret hyl ethyl ketone." The r esiilt'irig solutiori was heated'under reflux for four hours, and cooled to about room temperature. The crude hydrochloride was filtered off, dissolved in Water, the salaries nside alkaline with aqueous "sodium hydrex'ideandextrac'ied'three"times 0 nilliliter tion's of ether.-' "The""organic-extracts were c mbined; dried, the solvent removed by distillation, and the due distilled at a reduced pressure. There was thusobtained 10.6 grams of 2- (3;3-;di methy1pym0lifl -.ethyl 2,6-dimethyl-4-(n5propoxy)benzoate, boiling at; 2143 e re e t g ade a p es mf 0413 minimi e mercury absolute." j

Analysis:

CalculatedfopC-zqI-InQaN;- N,.--4-20 Found: 4.38'

Example r -Gidimsth py alidyll thyl 2.61: eih -fl-tnmao di nzoa l y b hl fide fslightex ssofdry hydrogen chloride gas was added to five grams of 2-(3,3-dirnethylpyrrolidyl1)-ethyl 2,6- dimethyl-4-(n-propoxy)benzoate in 50 milliliters 1ot d ry ethyl ether. The .etheLwasdecanted-and theoily'precipitate crystallized from ethyl acetate. There'was' thus obtained 4.7 grams'o'f 2-(3,3-dimethylpyrrolidyl-1)-ethyl 2,-6-dimethyl-4-(n-p opoxflbenmate hydhochlonideflmelting at 175 to 176.5 degrees centigrade. Analysis: Calculated foil CabHaiOiNClz Cl) 91 58 P Found: 9.6411

Analysis:

Calculated for C18H27N031 N, 4.58 Found: 2 4.58-

The hydrochloride melted at 148.5 to 151 degrees centii 8:;.--;iur. a Y Aimilysiszna;

ialculatedltar amends-01: N, 4.46 Found: 4.77

ji a: propoxybenzoatQboiling at 131 degrees c entigradeat a pressure of 0.03' millimeter of mercury absolute, Inf,

laws-t- Analysis: I Calculated f r t HtllNQaFN, 455 i I 1 I Found: *1 4.82

The hydrochloride melted at 166 to 167 degrees centigrade 1 propoxy) -benzoate, boiling at 154.5 to 155 degreescentigrade at a pressure of 0.07 millimeter of mercury n 1.5162.

Analysis Calculated for cmmmoai N, 4.38 Found: 4.52

absolute,-

Analysis: i a

Calculated for C19HsoNO3Cl: ,Cl,.9.96 Found: 10.0

4. 2-(3-methylpyrrolidyl-1)-ethyl 2,6- dimethyl-isopropoxy-benzoate, boiling at 141142 degrees centigrade at a pressure of 0.03 millimeter of mercury absolute, r1 1.5130.

Analysis:

7 Calculated for CmHzQNOz: N, 4.38 Found: 4.47

The hydrochloride melted at 148 to 149 degrees centigrade.

Analysis: 7

Calculated for CmHsoNOaCl: Cl, 9.96 Found: 9.86

5. Z-(Z-methylpyrrolidyl-l)-ethyl 2,6-dimethyl-4-(npropoxy)benzoate, boiling at 163.5 to 164 degrees centigrade at a pressure of 0.05 millimeter'of mercury absolute, 11 1.5162.

Analysis:

Calculated for C19Hz9NOa: N, 4.38 Found: 4.56

The hydrochloride melted at 163 to.164 degrees centi-. grade. 1

Analysis:

Calculated for CmHanNOaCl: Cl, 9.96 Found: 10.1

6. 2-(2-methylpyrrolidyl-1)-ethyl 2,6-dimethyl-4-isopropoxybenzoate, boiling at 143 degrees centigrade at a pressure of 0.03 millimeter of mercury absolute, n

Analysis Calculated for'CmHzsNOs: N, 4.38 Found: 4.48

The hydrochloride melted at 180 to 187.5 degrees centigrade.

Analysis: H 7 Calculated for C19H30NO3C1: Cl, 9.96.. Found: 10.0

7. 2-(3,3-dimethylpyrrolidyl-1)-ethyl 2,6-dimethyl-4- isopropoxybenzoate, boiling at 154 to 155 degrees centigrade at a pressure of 0.4 millimeter of mercury absolute, 11 1.505s.

8. 2-(2,5-dimethylpyrrolidyl-1)-ethy1 2,6 dimethyl 4- (n-propoxy)benzoate, boiling at 159.5 to 160 degrees centigrade at a pressure of 0.05 millimeter of mercury absolute, 11 1.5121. a I

Analysis:

Calculated for C2oH31NO3:'N,-4.20 Found: 4,44

lute, n 1.5113. Analysis:

Calculated for CznHsrNOa: N, 4.20 Found: a 4.15 15 The hydrochloride melted at 202 to 204 degrees centigrade.

Analysis:

Calculated for CzoHszNOsCl: Cl, 9.58 Found: 9.61 10. 2-(pyrrolidyl-1)-l-propyl 2,6-dimethyl 4 (n-propoxy)benzoate, boiling at 166 degrees centigrade at a pressure of 0.04 millimeter of mercury absolute, n 1.5192.

25 Analysis:

Calculated for CisHzsNOs: N, 4.38 Found: 4.36

The hydrochloride melted at 149-1505 degrees centigrade.

Analysis:

Calculated for CisHzoNoaClz Cl, 9.96 Found: 10.0

11. 2-(pyrrolidyl-1)-l-propyl 2,6 dimethyl 4 isopropoxybenzoate,.boiling at 143 to 144 degrees centigrade at a pressure of 0.05 millimeter of mercury absolute, n 1.5180.

Analysis: 40 Calculated for C19H29NO3: N, 4.38 Found: 4,42

The hydrochloride melted at 174 to 175 degrees centigrade.

Analysis: Calculated for C19H30NO3C1; Cl, 9.96

Found: 9.74

12. 1(pyrrolidyl-1)-2-propyl 2,6-dimethyl-4-(n-propoxy) benzoate, boiling at 132 degrees centigrade at a pressure of 0.05 millimeter of mercury absolute, n 1.5135.

Analysis: Calculated for Ciel-129N032 N, 4.38 Found: 4.20 The hydrochloride melted at 178 to 179 degrees centigrade.

Analysis:

Calculated for CisHsoNOzCl: Cl, 9.96 Found: 9.96

13. 1 (pyrrolidyl 1 Z-propyl 2,6-dimethyl-4-isopropoxybenzoate, boiling at 139 to 140 degrees centigrade at a pressure of 0.05 millimeter of mercury absolute, 11 1.5147.

5 Analysis: v

Calculated for C19H29NO3: N, 4.38 'Found: 4.36

The hydrochloride melted at 194 to 197 degrees centigrade. 0 Analysis:

Calculated for CiaHanNOaCl: Cl, 9.96 I Found: 9.92 i

14. 3 (pyrrolidyl 1) 2-buty1 2,6-dimethyl-4-(n-propoxy)benzoate, boiling at 143 to 144 degrees centigrade 12 The hydrochloride melted at to 186 degrees centigrade. Analysis:

Calculated for CznHszNOsCl: Cl, 9.58 Found: 9.38

9. 2-(2,5-dimethylpyrrolidyl-1)-ethyl 2,6-dimethyl-4- isopropoxybenzoate, boiling at 142 to 143 degrees centigrade at a pressure of 0.03 millimeter of mercury absoat a pressure of 0.03 millimeter of mercury absolute, n 1.5179.

Analysis: .1

Calculated for C2oH31N03: N, 4.20 Found: 4.07

The hydrochloride melted; #3182 10 1 83 degrees centig ade.

Analysis:

Calculated for CzoHzzNOsCl: Cl, 9.58 Found: 9.45

15. 3 (pyrrolidyl 1)-2-butyl 2,6-dimethyl4-isopropoxybenzoate, 'boiling at 155 to 156 degrees Centigrade at a pressure of 0.07 millimeterof mercury absolute, 12 1.5162. 1

Analysis: I g

Calculated for CzdHnNOa: N, 4.20 Found: 4.36

The hydrochloridemelted at 134 140 degrees centigrade.

Analysis:

. Calculated for CzoHazNOaCl: Cl, 9.58

Found:

16. 2-methyl-2-(pyrrolidyl-1)-1-propyl 2,6-dimethyl-4- (n-propoxy)benzoate, boiling at 142.5 to 143.5 degrees centigrade at a pressure of 0.03 millimeter of mercury absolute, n 1.5190.

Analysis:

- Calculated for CzoH'srNOa: N, 4.20 Found: 4.13

The hydrochloride melted at 175 to 176 degrees centigrade.

Analysis:

Calculated'for CzoHszNOa'Cl: Cl, 9.58 Found: 9.61

l7. 2-methyl-2-(Py1'rQlidyl-1)-1-propyl 2,6-dimethyl-4- isopropoxybenzoate, boiling at 144 to 145 degrees centigrade at. a pressure of 0.03 millimeter of mercury absolute.

Analysis:

Calculated for CzoHsiNOaz N, 4.20 Found: 4.04

The hydrochloride melted at 199 to 201 degrees centigrade.

Analysis:

Calculated for C20H32NO3C1: Cl, 9.58 Found: 9.66

18. 3 (pyrrolidyl 1)-1-propyl 2,6-dimethyl-4-(n-propoxy)benzoate, boiling at 151.5 to 152 degrees centigrade at a pressure of 0.07 millimeter of mercury absolute, 21 1.5176.

Analysis:

Calculated for C19H29NO3: N, 4.38 Found: 4.40

The hydrochloride melted at 150.5 to 152 degrees centigrade.

Analysis:

Calculated for CrsHsoNOaCl: Cl, 9.96 Found: 9.86

19. 3 (pyrrolidyl l) l-propyl 2,6-dimethyl-4-isopropoxybenzoate, boiling at 146 to 147 degrees centigrade at a pressure of 0.03 millimeter of mercury absolute, n 1.5157.

Analysis:

' Calculated for C19H29NO3: N, 4.38 4.44

Found:

. lute, n 1.5144.

1 14 The y hl rid'emelted at.162 to1163 degrees s grade. v v

Analysis:

Calculated for C19H30NO3C1: Cl, 9.96 Found: 990

Analysis:

Calculated for CzoHazNOaCl: CI, 9.5 8 Found: 9.69

2l.,3-.'( pyrrolidyl 1) -1-butyl 2,6 d-imethyl-4-isopropoxybenzoate, boiling at 146 to '147 degrees cent-igradeat a pressure of 0.03 millimeter of mercury absolute, n 1.5181.

Analysis= 5.1; 15:: v Calculated gfor C2oH31NO3: N, 4.20 ..-4- 8 hydrochloride me1ted-.at-111:5 5 112.5, degrees centigfadfl s Jx- 1 Analysis fi I Calculated for C2'oH3aNO3Cl: Cl, 9.58 Found; 9.53" t 22.52-methyl-34pyrrolidyl-1)-l-propyl 2,6-dimethyl-4- (n-propoxy)benz9ate, boiling at to- 14 1 degrees cen tigrade at a pressure of 0.04 millimeter of mercury abso- Analysis: i I

Calculated for CzoHarNOxi N, 4.20 :Found: i 1 l 4125 The hydrochloride melted at 13 1to132'degrees .centi grade. Analysis:

Calculated for C20H32NO3C1: Cl, 9.58

Found: 9.67

23. 2-methyl-3-(pyrrolidyl-1)-1-propyl 2,6-dimethyl-4- isopropoxybenzoate, boiling at 153 to 154 degrees centigrade at a pressure of 0.05 millimeter of mercury absolute, n 1.5155.

Analysis:

Calculated for C20H31NO3: N, 4.20 Found: 4.08

The hydrochloride melted at 156 to 157 degrees centigrade.

Analysis:

Calculated for CzoHazNOsCl: Cl, 9.58 Found: 9.61

24. 3 (Z-methylpyrrolidyl-l)-1-propyl 2,6-dimethyl-4- (npropoxy)benzoate, boiling at to 146 degrees centigrade at a pressure of 0.02 millimeter of mercury absolute, n 1.5165.

Analysis:

Calculated for C2oH31NO3: N, 4.20 Found: 4.23

The hydrochloride melted at 178 to 179 degrees centigrade.

Analysis:

Calculated for CzoHszNOaCl: Cl, 9.58 Found: 9.64

25. 3 (Zqnethylpyrrolidyl-l)-1-propyl 2,6-dimethyl-4- isopropoxybenzoate, boiling at 164 to 165 degrees centigrade at a pressure of 0.1 millimeter of mercury absolute, n ,1.5145.

Analysis:

Calculated for CH31NO3: N, 4.20 Found: 4.33

The hydrochloride metled at 191.5 to 193 degrees centigrade.

Analysis:

Calculated for CzoHazNOaCl: Cl, 9.58 Found: 9.42

I 26. 4 (pyrrolidyl 1) l-butyl 2,6-dimethyl-4-(n-propoxy)benzoate hydrochloride, melting at 103 to 104 degrees Centigrade.

Analysis:

Calculated for C20H32NO3C1: Cl, 9.58 Found: 9.77

27. 4 (pyrrolidyl 1) l-butyl 2,6-dimethyl-4-isopropoxybenzoate hydrochloride, melting at 110.5 to 112 degrees centigrade.

Analysis:

Calculated for CzuHazNOsCl: Cl, 9.5 Found: 9.61

ROG-C o 00.2mm

wherein R is a propyl group, R is a member of the group consisting of pyrrolidyl-l and loWer-alkyl-substituted pyrrolidyl-l, n is an integer from 2 to 5, inclusive; and (b) acid addition salts thereof with acids.

.16 2. A compound represented by the formula:

RO ooocnihnf wherein R is a propyl group, R is pyrrolidyl-l, and n is an integer from 2 to 5, inclusive.

3. An acid addition salt of a compound represented by the formula:

. CHa

wherein R is a propyl group, R is pyrrolidyl-l, and n is an integer from 2 to 5, inclusive.

4. 1 (Pyrrolidyl 1)-2-propyl 2,6-dimethyl-4-(n-propoxy)benzoate. i

5. 2 (Pyrrolidyl 1)-1-propyl 2,6-dimethyl-4-(n-propoxy)benzoate. v

6. 2 Methyl-Z-(pyrrolidyl-l)-l-propyl 2,6-dimethyl-4- (n-propoxy)benzoate.

7. 3 (Pyrrolidyl 1) 2-butyl 2,6-dimethy1-4-.(n-propoxy) benzo ate.

8. 4 (Pyrrolidyl 1) l-butyl 2,6-dimethyl-4-(n-propoxy)benzoate hydrochloride. 7

9. A compound represented by the formula:

wherein R is a propyl group, R is a lower-alkyl-substituted pyrroliclyl-l, and n is an integer from 2 to 5,'inclusive.

' Blicke et al.: Jr. Am. Chem. Soc., vol. 53 (March 1931), pp. 1015-25.

Moore: .Tr. Am. Pharm. Ass0c., vol. 33 (July Scientific Edition, pp. 193-204. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF (A) COMPOUNDS REPRESENTED BY THE FORMULA: 